The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 15, 2026 has been entered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 2-9, 16, 21-30 are canceled. Claims 1, 10-15, 17-20 are under consideration.
Priority: This application is a CON of U.S. Application 16320137, filed January 24, 2019, now U.S. Patent 11708570, which is a 371 of PCT/US17/44104, filed July 27, 2017, which claims benefit of provisional application 62/367321, filed July 27, 2016.
Objections and Rejections
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 10-15, 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Madison et al. (US 20160201047; IDS 03.01.23, previously cited). Madison et al. disclose modified Factor IX (FIX) polypeptides having improved procoagulant therapeutic properties, including increased activity and increased half-life (at least paragraphs 0007). Madison et al. disclose the modified FIX polypeptides contain one or more amino acid replacement(s) selected from positions including F342, T343, or E410 (at least paragraph 0008). Madison et al. disclose the modified FIX polypeptides comprise the FIX light chain and the FIX heavy chain, and further discloses the SEQ ID NOS. comprising the light chain and the heavy chains (at least paragraphs 0121-0122). Madison et al. disclose the amino acid replacements at E410 are selected from among E410K, E410R, E410Y (at least paragraph 0008), E410H (p. 50 paragraph 0419). While Madison et al. disclose the substitution at position E410 among other amino acid substitutions, it is expressly disclosed in Madison et al. that some of the variants displayed markedly increased catalytic activity compared to wild-type FIXa, including single amino acid substitutions FIXa-R338E, FIXa-R338A, FIXa-T343R, FIXa-E410N, and combinations thereof, such as at least R338E with E410N (paragraph 0602). It is disclosed that single amino acid substitutions at position E410 have an increased catalytic activity including 297% for E410N (p. 83 Table 14), 269% E410Q, 246% E410S, 248% E410A, 134% E410D (p. 85 Table 14). It is disclosed that single amino acid substitutions at positions R338 also have markedly increased catalytic activity, 361% R338A and 408% R338E (p. 84 Table 14), and further that the double amino acid substitutions at R338E/E410N have a significantly increased catalytic activity of 1018% (p. 84 Table 14). Madison et al. also disclose the amino acid replacement at R338 is selected from among at least R338L (at least paragraphs 0010, 0011, 0014)
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to arrive at the claimed FIX variant comprising a light chain and a
heavy chain, and wherein E410 (i.e. E265 of instant SEQ ID NO: 3) is substituted with Lys and R338 (i.e. R193 of instant SEQ ID NO: 3) is substituted with Leu (instant claim 1). The motivation to do so is given by Madison et al., which disclose and identify amino acid replacements in modified FIX polypeptides improve the therapeutic properties of FIX proteins, including increased activity and increased half-life, where the double amino acid substitution at position E410 and R338 has significantly increased catalytic activity compared to wild-type FIXa. One of ordinary skill would have a reasonable expectation of success because Madison et al. disclose and identify specific amino acid replacements within FIX polypeptides that contribute to improved properties.
Regarding instant claim 11, Madison et al. also disclose including the activated form of the modified FIX polypeptides (at least paragraph 0122).
Regarding instant claim 10, Madison et al. disclose compositions comprising said modified FIX polypeptides and at least one pharmaceutically acceptable carrier (at least paragraph 0035).
Regarding instant claims 12-14, Madison et al. disclose methods of treatment of a hemostasis related disorder comprising administering said modified FIX polypeptides (at least paragraphs 0541-0551), where the disorder is hemophilia B (at least paragraphs 0552-0561), to a subject.
Regarding instant claim 15, 17-19, Madison et al. disclose nucleic acid molecules encoding said modified FIX polypeptides, expression vectors comprising the nucleic acid molecules, host cells comprising the nucleic acid molecules, and methods of expressing the modified FIX polypeptides (at least paragraphs 0436-0467). Regarding instant claim 20, Madison et al. disclose methods of treatment comprising administering an expression vector comprising the nucleic acid molecules encoding said modified FIX polypeptides (at least paragraphs 0528-0540), to a subject, the vector being an adeno-associated virus vector (at least paragraph 0532).
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining the 103 rejection are the same as previously noted and are incorporated herein.
Instant claim 1 is drawn to a Factor IX variant, wherein the Factor IX variant comprises a light chain and heavy chain, wherein the light chain comprises SEQ ID NO: 2, wherein the heavy chain comprises SEQ ID NO: 3, where amino acid residues in SEQ ID NO: 3 are substituted and the amino acid substitutions are E265K/R193L, which corresponds to E410K/R338L in the numbering used in Madison et al.
For the purposes of the arguments made herein, the instant amino acid positions and/or substitutions will be referred to according to the numbering used in Madison et al.
Regarding Applicants’ remarks on the E410K/R338L substitution, Applicants assert that in Table 14 of Madison et al., the Factor IX variant is a double substitution R338E/E410N and not the R338L/E410K recited in the instant claims. Applicants assert that notably, Table 15 of Madison et al. teach that the Factor IX variant with the R338E/410N has an activity of 950% of wildtype – not the 1018% noted by the examiner in Table 14. Applicants then assert that all of the other substitutions at position 410 performed worse than E410N. Applicants assert that Table 15 indicates that E410Q, E410S, E410A, and E410D had activity that was 261%, 239%, 241%, and 130% of wild-type, respectively. Applicants assert that based on this data, why would the skilled artisan replace the asparagine at position 410 of Madison et al. with another amino acid?
Applicants’ remarks are not persuasive. It is known that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123.
In this instance, and also previously noted by Applicants, all the substitutions at positions E410 and R338, combined in Madison et al., are Factor IX variants having a much greater catalytic activity than the wildtype Factor IX, i.e. 1018% in Table 14 and 950% in Table 15. Even the single E410 substitutions noted by Applicants in Table 15 have greater catalytic activity than the wildtype Factor IX. Therefore, it is not clear how Madison et al. would teach away from amino acid substitutions at the amino acid positions E410 and R338.
As previously noted, one of ordinary skill would not need to consider all the combinations asserted by Applicants to arrive at the claimed FIX variant because Madison et al. expressly disclose which variants at which positions display markedly increased catalytic activity compared to wild-type FIXa, thereby providing guidance to arrive at the same positions recited.
While Madison et al. do disclose other amino acid substitutions along with position E410, it is expressly disclosed in Madison et al. that some of the variants displayed markedly increased catalytic activity compared to wild-type FIXa, including single amino acid substitutions FIXa-R338E, FIXa-R338A, FIXa-T343R, FIXa-E410N, and combinations thereof, such as at least R338E with E410N (paragraph 0602). It is disclosed that single amino acid substitutions at position E410 have an increased catalytic activity including 297% for E410N (p. 83 Table 14), 269% E410Q, 246% E410S, 248% E410A, 134% E410D (p. 85 Table 14). It is disclosed that single amino acid substitutions at positions R338 also have markedly increased catalytic activity, 361% R338A and 408% R338E (p. 84 Table 14), and further that the double amino acid substitutions at R338E/E410N have a significantly increased catalytic activity of 1018% (p. 84 Table 14).
Therefore, Madison et al. have clearly identified that amino acid substitutions at positions E410 and R338 of a FIX variant has significantly increased catalytic activity compared to wild-type FIXa; and, it would have been obvious to arrive at a FIX variant where the amino acid residues at positions E410 and R338 are substituted with a different amino acid residue, in view of Madison et al.
As noted above, Madison et al. disclose the amino acid replacement at R338 is selected
from among at least R338L (at least paragraphs 0010, 0011, 0014). As noted above, Madison et
al. disclose the amino acid replacement at E410 can also be selected from among E410K, E410R,
E410Y, E410H (at least paragraph 0008, 0419). Therefore, it would have been obvious to arrive
at the recited amino acid substitutions R338L and E410K and E410K/R338L, where one of
ordinary skill would have reasonable expectation that the combination of E410K/R338L in a FIX
variant also has significantly increased catalytic activity because Madison et al. has already
disclosed that a FIX variant having substitutions at just positions E410 and R338 has
significantly increased catalytic activity of 1018% (paragraph 0602, p. 84 Table 14).
Therefore, Applicants’ remarks that Madison et al. is completely void of any guidance for
the skilled artisan to combine a substitution at the Glu at position 410 with Lys and a substitution of the Arg at position 338 with Leu, are not persuasive.
In this instance, arriving at alternative amino acid substitutions at the E410 position, including the recited E410K substitution and R338L substitution, in the FIXa-R338E/E410N
variant of Madison et al. would have been obvious because Madison et al. has already disclosed
these same amino acid substitutions for position E410 and further exemplify that a FIX variant
having double amino acid substitutions at positions R338 and E410 has a significantly increased
catalytic activity of 1018% (p. 84 Table 14).
Applicants assert that Madison et al. repeatedly demonstrate that the replacement of negatively charged amino acid for a positively charged amino acid – or vice versa – in a FIX variant often destroys the activity of the FIX variant. Applicants assert that for example, Madison et al. provide the examples in Table 15 showing the activity of FIX variants compared to wild-type. Applicants list the FIX variants R318E – 37%, R403E – 12%, K400E – 21%, K293E – 17%, R333E – 0%, K316E – 2%, E239R – 122%, E239K – 111%.
Applicants’ remarks are not persuasive. The substitutions noted by Applicants are not even at the same positions R338 and E410, which has been identified by Madison et al. as having significantly increased catalytic activity (see teachings of Madison et al. above). Madison et al. has disclosed that FIX variants having substitutions at positions R338 and E410 have significantly increased catalytic activity (paragraph 0602) and further disclose R338 is selected
from among at least R338L (at least paragraphs 0010, 0011, 0014) and the amino acid replacement at E410 can also be selected from among E410K, E410R, E410Y, E410H (at least paragraph 0008, 0419).
As previously noted, there is no requirement under 103 that a reference must supply actual data or exemplify all embodiments taught.
Therefore, arriving at alternative amino acid substitutions at the E410 position, including the recited E410K substitution and R338L substitution, in the FIXa-R338E/E410N
variant of Madison et al. would have been obvious because Madison et al. has already disclosed
these same amino acid substitutions for position E410 and further exemplify that a FIX variant
having double amino acid substitutions at positions R338 and E410 has a significantly increased
catalytic activity of 1018% (p. 84 Table 14).
Therefore, Applicants’ remarks that Madison et al. demonstrate that the replacement of negatively charged amino acid for a positively charged amino acid – or vice versa – in a FIX variant often destroys the activity of the FIX variant are not found persuasive because the substitutions noted by Applicants are not in the same positions R338 and E410, which has been identified by Madison et al. as having significantly increased catalytic activity (see above).
Regarding Applicants that all of the other substitutions at position 410 performed worse than E410N in Madison et al., the remarks are not persuasive because all the other substitutions at E410 still demonstrated increased catalytic activity to wild-type FIXa (p. 83 Table 14, p. 85 Table 14). Therefore, Applicants have not demonstrated that substitution of another amino acid residue as suggested in Madison et al., besides N, at position E410 destroys the activity of the FIX variant and renders the FIX variant unsatisfactory for its intended purpose.
Applicants assert that the present application has demonstrated that the Factor IX variant comprising E410K and R338L possesses unexpectedly superior properties. Applicants assert that Table 1 of the present application provides the activity level (specific activity) of the tested Factor IX variants compared to wild-type Factor IX. Applicants assert that significantly, the combination of the E410K and R338L substitutions resulted in a Factor IX activity that was surprisingly 17-fold greater than wild-type. Applicants assert that Madison et al. fail to synthesize and characterize Factor IX variants comprising an E410K. Applicants assert that rather, Madison et al. tested the substitutions E410N, E410Q, E410S, E410A, and E410D. Applicants assert that as seen in Table 14 of Madison et al., the catalytic activity of these Factor IX variants of Madison et al. only show an activity which is 134% to 297% of wild-type (i.e., less than a threefold increase).
Applicants’ remarks are not persuasive.
MPEP 716.01(c) notes that objective evidence which must be factually supported by an
appropriate affidavit or declaration to be of probative value includes evidence of unexpected
results, commercial success, solution of a long-felt need, inoperability of the prior art, invention
before the date of the reference, and allegations that the author(s) of the prior art derived the
disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re
De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that
unexpected results must be established by factual evidence." "[A]ppellants have not presented
any experimental data showing that prior heat-shrinkable articles split. Due to the absence of
tests comparing appellant's heat shrinkable articles with those of the closest prior art, we
conclude that appellant's assertions of unexpected results constitute mere argument."). See also
In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21
USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
Further, the arguments of counsel cannot take the place of evidence in the record. In re
Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements
which are not evidence and which must be supported by an appropriate affidavit or declaration
include statements regarding unexpected results, commercial success, solution of a long-felt
need, inoperability of the prior art, invention before the date of the reference, and allegations that
the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one
joint inventor.
Further, MPEP 716.02(b) notes that Applicant has the burden to establish that the results
are unexpected and significant. Evidence of unexpected properties may be in the form of a direct
or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See also MPEP 716.02(e) noting that the claimed subject matter has to
be compared with the closest prior art to be effective to rebut a prima facie case of obviousness.
In this instance, Applicants have not provided a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. The closest prior art is the FIX variant with double amino acid substitutions at R338E/E410N of Madison et al. (p. 84 Table 14).
Regarding Applicants’ remarks on the assays used to measure “catalytic activity” in Madison et al. and the assays in the examples of the instant specification, Applicants previously asserted that inasmuch as the assay of Madison et al. and the assay of the instant application both measure the activity of the FIX variant by determining the variant’s ability to form the Xase complex and to cleave and activate FX, Applicants submit that these assays are comparable. Applicants assert that the examiner has failed to provide any scientific basis to the contrary.
Applicants’ remarks are not persuasive. As previously noted, it is expressly disclosed and acknowledged in the prior art that an “activity” of a FIX polypeptide refers to any activity exhibited by a FIX polypeptide; such activities can be tested in vitro and/or in vivo and include, but are not limited to, coagulation or coagulant activities, pro-coagulant activity, proteolytic or catalytic activity such as to effect FX activation (Madison et al. paragraph 0138).
Madison et al. disclose “coagulation activity" or "coagulant activity" or "pro-coagulant activity" refers to the ability of a polypeptide to effect coagulation. Assays to assess coagulant activity are known to those of skill in the art, and include prothrombin time (PT) assay or the activated partial thromboplastin time (aPTT) assay (at least paragraph 0141).
Madison et al. disclose "catalytic activity" or "proteolytic activity" with reference to FIX refers to the ability of a FIX protein to catalyze the proteolytic cleavage of a substrate, and are used interchangeably. Assays to assess such activities are known in the art (at least paragraph 0142).
Therefore, it is acknowledged that the different activities of FIX, including “coagulation” (or “clotting”) activity and “catalytic” activity are measured on different assays and assessed differently.
The instant specification at examples 1 and 2 disclose assessing the FIX variants by a FIX specific clotting assay and an aPTT-based clotting assay. As noted above, Madison et al. disclose clotting assays, including aPTT assays are for assessing coagulating activity (at least paragraph 0141). Therefore, the assays used in the instant specification are measuring coagulant activity or clotting activity of the FIX variants, which is a different activity than what is being measured in Table 14 of Madison et al. Table 14 of Madison et al. shows the markedly increased catalytic activity of the FIX variants compared to wild-type FIXa, which are measured with assays using synthetic substrates (at least paragraphs 0142, 0595). The assays in examples 1 and 2 of the instant specification for measuring coagulant activity are materially and functionally different than the assays for measuring the catalytic activity of the FIX variants in Table 14 of Madison et al.
Regarding Applicants’ remarks that the data from the assays in Madison et al. and the instant application are both normalized against wild-type FIX activity, the remarks are not persuasive. The activity presented in Table 14 of Madison et al. is FIX catalytic activity and is assessed by an assay that is completely different than the assays in examples 1-2 of the instant application, which are assays assessing FIX coagulant activity.
Therefore, Applicants’ remarks that the assays measure comparable activities and functionalities and are properly comparable for purposes of showing unexpectedly superior results are not found persuasive.
Applicants’ remarks regarding the difference in fold increase between the activity tested in Madison et al. and the instant specification are not persuasive because different activities or functionalities are being tested and are not properly compared.
Applicants assert that the present application has demonstrated that the Factor IX variant comprising E410K and R338L possesses unexpectedly superior properties. Applicants assert that Table 1 of the present application provides the activity level (specific activity) of the tested Factor IX variants compared to wild-type Factor IX. Applicants assert that significantly, the combination of the E410K and R338L substitutions resulted in a Factor IX activity that was surprisingly 17-fold greater than wild-type. Applicants assert that Madison et al. fail to synthesize and characterize Factor IX variants comprising an E410K. Applicants assert that rather, Madison et al. tested the substitutions E410N, E410Q, E410S, E410A, and E410D. Applicants assert that as seen in Table 14 of Madison et al., the catalytic activity of these Factor IX variants of Madison et al. only show an activity which is 134% to 297% of wild-type (i.e., less than a threefold increase).
Applicants’ remarks regarding unexpectedly superior activity are not persuasive because
this is not a proper comparison. Madison et al. is testing the catalytic activity of the substitutions, including the E410 substitutions, in Table 14. In Table 1 of the instant specification, example 1 discloses that the specific activity being tested is clotting activity
(paragraph 0074). Therefore, Applicants’ remarks regarding the difference in fold increase
between the activity tested in Madison et al. and the instant specification are not persuasive
because different activities or functionalities are being tested and are not properly compared.
Further, MPEP 716.02(b) notes that Applicant has the burden to establish that the results
are unexpected and significant. Evidence of unexpected properties may be in the form of a direct
or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See also MPEP 716.02(e) noting that the claimed subject matter has to
be compared with the closest prior art to be effective to rebut a prima facie case of obviousness.
In this instance, Applicants have not provided a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. The closest prior art is the FIX variant with double amino acid substitutions at R338E/E410N of Madison et al. (p. 84 Table 14).
Therefore, Applicants’ assertion of unexpectedly superior activity (table 1 of specification) would flow naturally from following the suggestion of the prior art. See also MPEP 2145. "The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
As noted above, Madison et al. has already disclosed that a FIX variant having
substitutions at just positions E410 and R338 (R338E/E410N) has significantly increased
catalytic activity (1018%) compared to wild-type FIX (paragraph 0602, p. 84 Table 14). Madison et al. further disclose the amino acid replacement at R338 is selected from among at least R338L (at least paragraphs 0010, 0011, 0014) and the amino acid replacement at E410 can also be selected from among E410K (at least paragraph 0008, 0419). Therefore, it would have been obvious to arrive at the recited amino acid substitutions R338L and E410K and E410K/R338L, where one of ordinary skill would have reasonable expectation that the combination of E410K/R338L in a FIX variant also has significantly increased catalytic activity because Madison et al. has already disclosed that a FIX variant having substitutions at just positions E410 and R338 has significantly increased catalytic activity of 1018% (paragraph 0602, p. 84 Table 14).
Therefore, Madison et al. provide guidance to arrive at a FIX variant where the amino acid residues at positions E410 and R338 are substituted with Lys (K) and Leu (L), respectively, which are the same positions and substitutions recited in instant claim 1.
Therefore, Applicants’ remarks on the E410K/R338L FIX variant are not found persuasive.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Marsha Tsay whose telephone number is (571)272-2938. The examiner can normally be reached on M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath N. Rao can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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